The Role of Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Derived Reactive Oxygen Species in the Acquisition of Metastatic Ability of Tumor Cells

Abstract

We examined the role of phagocyte-derived oxygen radicals in tumor cell acquisition of metastatic phenotype by comparing gp91(phox-/-) mice and C57BL/6J wild-type (WT) mice. The gp91(phox-/-) mouse is deficient in the gp91(phox) gene, an essential subunit of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase that generates superoxide anion. QR-32 fibrosarcoma cells are nonmetastatic but are converted into metastatic tumors once in contact with foreign body (gelatin sponge)-induced phagocytes in vivo. Compared to QR-32 cells co-implanted with the foreign body in WT mice, those in gp91(phox-/-) mice exhibited reduced metastasis. There was no difference in the incidence of primary tumors after injection of B16BL6 melanoma cells in WT and gp91(phox-/-) mice. However, after resection of the primary tumors, metastases were reduced in gp91(phox-/-) mice. Thymosin beta4 gene expression and cell motility/invasion were seen in the tumors from WT mice but not in those from gp91(phox-/-) mice. Adoptive transfer of phagocytes from WT mice, but not those from gp91(phox-/-) mice, restored the metastatic ability of tumors grown in gp91(phox-/-) mice. These findings show that tumor metastatic behavior can primarily be endowed by phagocyte-derived superoxide anion and its oxidative metabolites, which are generated through activation of nicotinamide adenine dinucleotide phosphate oxidase.

Beyond foreign‐body‐induced carcinogenesis: Impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression

“…In contrast, the phagocytes obtained from knockout mice did not have such activity. 98 Moreover, administration of aminoguanidine, a broad inhibitor for inducible nitric oxide synthase, partially but significantly suppressed malignant conversion in the model 93 ; thus we concluded that RNS were also involved in the process. These results show that ROS and RNS, derived from foreign-body-induced neutrophils, are an intrinsic factor in the conversion of regressive tumors to more malignant ones.…”

“…Moreover, acquisition of metastatic ability was reduced in the mice. 98 Thymosin ß4, a genetic marker of QR cell progression, 91 was not detected in the arising tumors in gp91 phox2/2 mice. To confirm whether phagocyte-derived ROS were actually involved in tumor progression, we isolated phagocytes from wild-type mice and transferred them into gp91 phox2/2 mice.…”

Nano-Scaled Particles of Titanium Dioxide Convert Benign Mouse Fibrosarcoma Cells into Aggressive Tumor Cells

“…We have previously revealed that the survived cell population from benign QR-32 cells was converted into aggressive tumor cells by inflammatory cell-derived ROS-and NOmediated injury. 29,30 The QR-32 cells used in the study are a typically sensitive clone to ROS injury because they contain less antioxidative enzymes (low in manganese superoxide dismutase and glutathione peroxidase activities), compared with ROS-resistant clones. 28 Therefore, we assumed that ROS-affected surviving cells would be prone to convert themselves into more malignant ones.…”

“…Detailed methods for isolating peritoneal exudate cells from mice were described in a previous report. 29 …”

“…As a positive control for this NO detection system, we measured peritoneal exudate cells (PEC) collected from the mice that had a foreign body implanted for 5 days. 29 While increased production of nitrite/nitrate was observed, this was inhibited by an inhibitor of inducible nitric oxide synthase, aminoguanidine (AG).…”